1. Field of the Invention
The present invention relates to a biocompatible amphiphilic poly(organophosphazene) that exhibits a temperature-dependent phase transition and a preparation method thereof.
2. Description of the Background Art
In general, thermosensitive polymers refer to polymers that exhibit a temperature-dependent phase transition from liquid (sol) to gel or precipitate in an aqueous solution. Such phase transition may be reversible or irreversible. Such phase transition behavior is ascribed to the fact that at a lower temperature, the polymer molecules are uniformly dispersed in an aqueous solution by strong hydrogen bonding between the solvent water molecules and the hydrophilic parts of the polymer, but as the temperature is raised, such hydrogen bonding is weakened, while the intermolecular interaction among the hydrophobic groups of the polymer molecules increases to form a physical network. If the polymeric net work is strong enough to retain the water molecules within the network, they form a gel, and the temperature at which the gel is formed is called “a gelation temperature.” However, if the network is not strong, the water molecules are expelled out of the polymer network, resulting in precipitation of the polymer. The temperature at which the precipitate is formed is called “a lower critical solution temperature (LCST).” The phase transition temperature of the thermosensitive polymers depends on the hydrophilic to hydrophobic balance of the polymer molecule, which is determined by both contents and structures of the hydrophilic and hydrophobic (i.e., lipophilic) groups of the polymer. In general, the higher the content of the hydrophilic groups, the higher the phase transition temperature, while the higher the content of the hydrophobic groups, the lower the phase transition temperature. Such thermosensitive polymers have a great potential for applications in many different areas such as drug delivery systems, medical, environmental and biological sciences, and the like. Representative examples of thermosensitive polymers are poly(N-isopropyl acrylamide), polyethylene oxide copolymer, hydroxy-containing polymers, and polyphosphazenes (K. Park Eds., Controlled Drug Delivery, 485 (1997)). However, it has been reported that most of the known thermosensitive polymers are not only toxic, but also non-biodegradable, and therefore, they are not suitable for drug delivery. Although the recently reported thermosensitive block copolymers consisting of poly(lactic acid) and poly(ethylene oxide) are biodegradable (B. Jeong et al., Nature, 388, 860 (1997)), they become acidic when degraded in vivo, which may denature the protein drugs. Therefore, these copolymers are also not suitable for delivery of protein drugs, which will be the major drugs in the future.
Polyphosphazene is an inorganic/organic hybrid polymer, which was firstly synthesized by Allcock group in the United States (H. R. Allcock and R. L. Kugel, J. Am. Chem. Soc., 87, 4216 (1965)). Polyphosphazene is a linear polymer in which its polymer backbone consists of alternating phosphorus and nitrogen atoms and organic substituents are linked to the phosphorus atoms as side groups, and exhibits a variety of different physical properties depending on the molecular structure of the side chains. Even though polyphosphazenes have good physical properties that organic polymers do not have, they could not have been widely used due to their high price, and therefore, only have been used for limited purpose. In particular, polyphosphazenes could not be developed as drug delivery systems because polyphosphazenes prepared for general purpose according to the conventional method developed by Allcock group are required to have a molecular weight higher than 106 (Mw>106) for strong mechanical properties, but it is well known that the upper limit of the polymer molecular weight for glomerular excretion is approximately 70,000 [K. Park Eds., Controlled Drug Delivery, 52 (1997)] and therefore, the molecular weight of polyphosphazenes as biocompatible drug delivery systems should be controlled below 100,000.
The present inventors have discovered and reported that if aluminum chloride is used as a catalyst in the synthesis of poly(dichlorophosphazenes) from hexachlorocyclotriphosphazene (N3P3Cl6) by thermal polymerization, it is possible to control the molecular weight of the chloropolymer depending on the amount of catalysts used (Youn Soo Sohn, et al., Macromolecules, 1995, 28, 7566), and have been developing various amphiphilic poly(organophosphazenes) therefrom for new drug delivery systems.
The present inventors have also reported that poly(organophosphazenes) obtained by stepwise nucleophilic substitutions of the chlorine atoms of poly(dichlorophosphazene) with a hydrophilic poly(ethylene glycol) and a hydrophobic amino acid exhibited thermosensitive properties by manifesting water-solubility under a certain temperature but precipitation above such temperature, and that these poly(organophosphazenes) are hydrolytically degradable in aqueous solution (Youn Soo Sohn, et al., Macromolecules, 1999, 32, 2188). However, it was found that these poly(organophosphazenes) mostly exhibited a phase transition temperature above body temperature, and in order to lower the phase transition temperature below body temperature, it was necessary to increase remarkably the mole fraction of the hydrophobic amino acid and/or to introduce more than two different types of amino acid esters. In particular, a poly(organophosphazene) gel with a gelation temperature below body temperature could be synthesized by employing α-amino-ω-methoxy poly(ethylene glycol) (AMPEG) instead of methoxy poly(ethylene glycol) (MPEG) (Youn Soo Sohn, et al., Macromolecules, 2002, 35, 3876), but animal experiments have shown that this gel was not biocompatible since this gel caused skin inflammation.